Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock

C. Thiemermann, C. C. Wu, Csaba Szabo, M. Perretti, J. R. Vane

Research output: Contribution to journalArticle

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Abstract

1. This study investigates the role of tumour necrosis factor (TNF) in the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in a rat model of endotoxin shock. 2. In anaesthetized rats, pretreatment with a monoclonal antibody for TNF (TNF(ab); 29 mg kg-1, s.c., at 16 h prior to LPS) ameliorated the fall in mean arterial blood pressure (MAP) in response to LPS (2 mg kg-1, i.v.). for instance, endotoxaemia for 180 min resulted in fall in MAP from 114 ± 6 (control) to 84 ± 5 mmHg (P < 0.01; n = 7). In contrast, animals pretreated with TNF(ab) prior to LPS injection maintained significantly higher MAP when compared to LPS-control (MAP at 180 min; 118 ± 3 mmHg; P < 0.01, n = 5). 3. Three hours of endotoxaemia was also associated with a significant reduction of the contractile effects of noradrenaline (NA) (10-8-10-6 M) on the thoracic aorta ex vivo. This hyporeactivity to NA was partially restored by in vitro treatment of the vessels with N(G)-nitro-L-arginine methyl ester (L-NAME, 20 min, 3 x 10-4 M). Pretreatment of rats with TNF(ab) (20 mg kg-1; at 16 h prior to LPS) significantly (P < 0.05) attenuated the LPS-induced hyporeactivity of rat aortic rings ex vivo. L-NAME did not enhance the contractions of aortic rings obtained from TNF(ab) pretreated LPS-rats. 4. At 180 min after LPS there was a significant elevation of the induced NOS activity in the lung (5.14 ± 0.57 pmol citrulline mg-1 min-1, n = 8). TNF(ab) pretreatment significantly attenuated this induction of NOS in response to LPS by 37 ± 6% (n = 5; P < 0.05). 5. We conclude that the formation of endogenous TNF contributes to the induction of the calcium-independent isoform of NOS in response to LPS in vivo. Thus, the beneficial effects of agents which inhibit either the release or the action of TNF in circulatory shock maybe, in part, due to inhibition of NOS induction.

Original languageEnglish (US)
Pages (from-to)177-182
Number of pages6
JournalBritish Journal of Pharmacology
Volume110
Issue number1
StatePublished - 1993
Externally publishedYes

Fingerprint

Endotoxins
Nitric Oxide Synthase
Shock
Tumor Necrosis Factor-alpha
Arterial Pressure
NG-Nitroarginine Methyl Ester
Endotoxemia
Norepinephrine
Citrulline
Thoracic Aorta
Lipopolysaccharides
Protein Isoforms
Monoclonal Antibodies
Calcium
Lung
Injections

Keywords

  • Aorta
  • Contraction
  • Endotoxin shock
  • Nitric oxide
  • Noradrenaline
  • Vasodilatation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. / Thiemermann, C.; Wu, C. C.; Szabo, Csaba; Perretti, M.; Vane, J. R.

In: British Journal of Pharmacology, Vol. 110, No. 1, 1993, p. 177-182.

Research output: Contribution to journalArticle

Thiemermann, C. ; Wu, C. C. ; Szabo, Csaba ; Perretti, M. ; Vane, J. R. / Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. In: British Journal of Pharmacology. 1993 ; Vol. 110, No. 1. pp. 177-182.
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AU - Vane, J. R.

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